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BACKGROUND & AIMS: Because inflammatory bowel disease is increasing worldwide and can lead to colitis-associated carcinoma (CAC), new interventions are needed. We have shown that spermine oxidase (SMOX), which generates spermidine (Spd), regulates colitis. Here we determined whether Spd treatment reduces colitis and carcinogenesis. METHODS: SMOX was quantified in human colitis and associated dysplasia using quantitative reverse-transcription polymerase chain reaction and immunohistochemistry. We used wild-type (WT) and Smox-/- C57BL/6 mice treated with dextran sulfate sodium (DSS) or azoxymethane (AOM)-DSS as models of colitis and CAC, respectively. Mice with epithelial-specific deletion of Apc were used as a model of sporadic colon cancer. Animals were supplemented or not with Spd in the drinking water. Colonic polyamines, inflammation, tumorigenesis, transcriptomes, and microbiomes were assessed. RESULTS: SMOX messenger RNA levels were decreased in human ulcerative colitis tissues and inversely correlated with disease activity, and SMOX protein was reduced in colitis-associated dysplasia. DSS colitis and AOM-DSS-induced dysplasia and tumorigenesis were worsened in Smox-/- vs WT mice and improved in both genotypes with Spd. Tumor development caused by Apc deletion was also reduced by Spd. Smox deletion and AOM-DSS treatment were both strongly associated with increased expression of α-defensins, which was reduced by Spd. A shift in the microbiome, with reduced abundance of Prevotella and increased Proteobacteria and Deferribacteres, occurred in Smox-/- mice and was reversed with Spd. CONCLUSIONS: Loss of SMOX is associated with exacerbated colitis and CAC, increased α-defensin expression, and dysbiosis of the microbiome. Spd supplementation reverses these phenotypes, indicating that it has potential as an adjunctive treatment for colitis and chemopreventive for colon carcinogenesis.
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Carcinogénesis/efectos de los fármacos , Carcinogénesis/genética , Colitis/genética , Neoplasias del Colon/genética , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/genética , Espermidina/uso terapéutico , Proteína de la Poliposis Adenomatosa del Colon/genética , Animales , Azoximetano , Colitis/inducido químicamente , Colitis/enzimología , Colitis/prevención & control , Colitis Ulcerosa/enzimología , Colitis Ulcerosa/genética , Colon/enzimología , Colon/patología , Neoplasias del Colon/prevención & control , Sulfato de Dextran , Microbioma Gastrointestinal/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Mucosa Intestinal/enzimología , Mucosa Intestinal/patología , Masculino , Ratones , Oxidorreductasas actuantes sobre Donantes de Grupo CH-NH/metabolismo , Lesiones Precancerosas/enzimología , Factores Protectores , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Espermidina/metabolismo , Espermidina/farmacología , Pérdida de Peso/efectos de los fármacos , alfa-Defensinas/genética , alfa-Defensinas/metabolismo , Poliamino OxidasaRESUMEN
A previous study revealed that treatment with the anticoagulant heparin attenuated concanavalin A (ConA)-induced liver injury. The administration of spermidine (SPD) increased urokinase-type plasminogen activator (uPA) levels in the serum. uPA is clinically used for the treatment of some thrombotic diseases such as cerebral infarction. Therefore, SPD may attenuate ConA-induced liver injury that is exacerbated by blood coagulation. The present study investigated the effect of SPD on liver injury in mice with autoimmune hepatopathy induced by ConA. A model of liver injury was created by intravenous injection of ConA into mice. SPD was administered in free drinking water and was biochemically and pathologically examined over time. The administration of SPD to ConA-treated mice significantly reduced liver injury. However, SPD treatment upregulated the mRNA expression of TNF-α and IFN-Ï in the livers of ConA-treated mice. In contrast, the mRNA expression of tissue factor in the livers of SPD-treated mice was decreased after ConA injection. The frequency of lymphocytes and lymphocyte activation were not affected by SPD administration in ConA-treated mice. SPD treatment increased uPA levels in the serum and decreased the level of D-dimer in ConA-treated mice. Moreover, SPD decreased fibrin in the livers of ConA-treated mice. These results indicated that SPD treatment increased anticoagulant ability by increasing of uPA and attenuated ConA-induced liver injury.
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Enfermedad Hepática Crónica Inducida por Sustancias y Drogas , Enfermedad Hepática Inducida por Sustancias y Drogas , Animales , Ratones , Concanavalina A/farmacología , Espermidina/farmacología , Espermidina/uso terapéutico , Espermidina/metabolismo , Enfermedad Hepática Crónica Inducida por Sustancias y Drogas/metabolismo , Hígado/metabolismo , Anticoagulantes/farmacología , ARN Mensajero/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoRESUMEN
BACKGROUND AND AIMS: Liver diseases present a wide range of fibrosis, from fatty liver with no inflammation to steatohepatitis with varying degrees of fibrosis, to established cirrhosis leading to HCC. In a multivariate analysis, serum levels of spermidine were chosen as the top metabolite from 237 metabolites and its levels were drastically reduced along with progression to advanced steatohepatitis. Our previous studies that showed spermidine supplementation helps mice prevent liver fibrosis through MAP1S have prompted us to explore the possibility that spermidine can alleviate or cure already developed liver fibrosis. METHODS: We collected tissue samples from patients with liver fibrosis to measure the levels of MAP1S. We treated wild-type and MAP1S knockout mice with CCl4 -induced liver fibrosis with spermidine and isolated HSCs in culture to test the effects of spermidine on HSC activation and liver fibrosis. RESULTS: Patients with increasing degrees of liver fibrosis had reduced levels of MAP1S. Supplementing spermidine in mice that had already developed liver fibrosis after 1 month of CCl4 induction for an additional 3 months resulted in significant reductions in levels of ECM proteins and a remarkable improvement in liver fibrosis through MAP1S. Spermidine also suppressed HSC activation by reducing ECM proteins at both the mRNA and protein levels, and increasing the number of lipid droplets in stellate cells. CONCLUSIONS: Spermidine supplementation is a potentially clinically meaningful approach to treating and curing liver fibrosis, preventing cirrhosis and HCC in patients.
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Carcinoma Hepatocelular , Hígado Graso , Cirrosis Hepática , Neoplasias Hepáticas , Animales , Ratones , Autofagia/fisiología , Carcinoma Hepatocelular/patología , Hígado Graso/patología , Fibrosis , Células Estrelladas Hepáticas/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/genética , Neoplasias Hepáticas/patología , Proteínas Asociadas a Microtúbulos/metabolismo , Espermidina/farmacología , Espermidina/uso terapéutico , Espermidina/metabolismo , HumanosRESUMEN
BACKGROUND: Acute kidney injury (AKI) is still a critical problem in clinical practice, with a heavy burden for national health system around the world. It is notable that sepsis is the predominant cause of AKI for patients in the intensive care unit and the mortality remains considerably high. The treatment for AKI relies on supportive therapies and almost no specific treatment is currently available. Spermidine is a naturally occurring polyamine with pleiotropic effects. However, the renoprotective effect of spermidine and the underlying mechanism remain elusive. METHODS: We employed mice sepsis-induced AKI model and explored the potential renoprotective effect of spermidine in vivo with different administration time and routes. Macrophage depleting was utilized to probe the role of macrophage. In vitro experiments were conducted to examine the effect of spermidine on macrophage cytokine secretion, NLRP3 inflammasome activation and mitochondrial respiration. RESULTS: We confirmed that spermidine improves AKI with different administration time and routes and that macrophages serves as an essential mediator in this protective effect. Meanwhile, spermidine downregulates NOD-like receptor protein 3 (NLRP3) inflammasome activation and IL-1 beta production in macrophages directly. Mechanically, spermidine enhances mitochondrial respiration capacity and maintains mitochondria function which contribute to the NLRP3 inhibition. Importantly, we showed that eukaryotic initiation factor 5A (eIF5A) hypusination plays an important role in regulating macrophage bioactivity. CONCLUSIONS: Spermidine administration practically protects against sepsis-induced AKI in mice and macrophages serve as an essential mediator in this protective effect. Our study identifies spermidine as a promising pharmacologic approach to prevent AKI.
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Lesión Renal Aguda , Sepsis , Lesión Renal Aguda/metabolismo , Animales , Modelos Animales de Enfermedad , Inflamasomas/metabolismo , Macrófagos , Ratones , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas NLR/metabolismo , Factores de Iniciación de Péptidos/metabolismo , Factores de Iniciación de Péptidos/farmacología , Factores de Iniciación de Péptidos/uso terapéutico , Respiración , Sepsis/metabolismo , Espermidina/metabolismo , Espermidina/farmacología , Espermidina/uso terapéuticoRESUMEN
BACKGROUND: Deposition of amyloid beta (Aß) and hyperphosphorylated tau along with glial cell-mediated neuroinflammation are prominent pathogenic hallmarks of Alzheimer's disease (AD). In recent years, impairment of autophagy has been identified as another important feature contributing to AD progression. Therefore, the potential of the autophagy activator spermidine, a small body-endogenous polyamine often used as dietary supplement, was assessed on Aß pathology and glial cell-mediated neuroinflammation. RESULTS: Oral treatment of the amyloid prone AD-like APPPS1 mice with spermidine reduced neurotoxic soluble Aß and decreased AD-associated neuroinflammation. Mechanistically, single nuclei sequencing revealed AD-associated microglia to be the main target of spermidine. This microglia population was characterized by increased AXL levels and expression of genes implicated in cell migration and phagocytosis. A subsequent proteome analysis of isolated microglia confirmed the anti-inflammatory and cytoskeletal effects of spermidine in APPPS1 mice. In primary microglia and astrocytes, spermidine-induced autophagy subsequently affected TLR3- and TLR4-mediated inflammatory processes, phagocytosis of Aß and motility. Interestingly, spermidine regulated the neuroinflammatory response of microglia beyond transcriptional control by interfering with the assembly of the inflammasome. CONCLUSIONS: Our data highlight that the autophagy activator spermidine holds the potential to enhance Aß degradation and to counteract glia-mediated neuroinflammation in AD pathology.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Espermidina , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/metabolismo , Animales , Modelos Animales de Enfermedad , Ratones , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Espermidina/farmacología , Espermidina/uso terapéuticoRESUMEN
Diabetes mellitus (DM), a high incidence metabolic disease, is related to the impairment of male spermatogenic function. Spermidine (SPM), one of the biogenic amines, was identified from human seminal plasma and believed to have multiple pharmacological functions. However, there exists little evidence that reported SPM's effects on moderating diabetic male spermatogenic function. Thus, the objective of this study was to investigate the SPM's protective effects on testicular spermatogenic function in streptozotocin (STZ)-induced type 1 diabetic mice. Therefore, 40 mature male C57BL/6 J mice were divided into four main groups: the control group (n = 10), the diabetic group (n = 10), the 2.5 mg/kg SPM-treated diabetic group (n = 10) and the 5 mg/kg SPM-treated diabetic group (n = 10), which was given intraperitoneally for 8 weeks. The type 1 diabetic mice model was established by a single intraperitoneal injection of STZ 120 mg/kg. The results showed that, compare to the control group, the body and testis weight, as well the number of sperm were decreased, while the rate of sperm malformation was significantly increased in STZ-induced diabetic mice. Then the testicular morphology was observed, which showed that seminiferous tubule of testis were arranged in mess, the area and diameter of which was decreased, along with downregulated anti-apoptotic factor (Bcl-2) expression, and upregulated pro-apoptotic factor (Bax) expression in the testes. Furthermore, testicular genetic expression levels of Sertoli cells (SCs) markers (WT1, GATA4 and Vimentin) detected that the pathological changes aggravated observably, such as the severity of tubule degeneration increased. Compared to the saline-treated DM mice, SPM treatment markedly improved testicular function, with an increment in the body and testis weight as well as sperm count. Pro-apoptotic factor (Bax) was down-regulated expression with the up-regulated expression of Bcl-2 and suppression of apoptosis in the testes. What's more, expression of WT1, GATA4, Vimentin and the expressions of glycolytic rate-limiting enzyme genes (HK2, PKM2, LDHA) in diabetic testes were also upregulated by SPM supplement. The evidence derived from this study indicated that the SMP's positive effect on moderating spermatogenic disorder in T1DM mice's testis. This positive effect is delivered via promoting spermatogenic cell proliferation and participating in the glycolytic pathway's activation.
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Diabetes Mellitus Experimental , Glucólisis/efectos de los fármacos , Infertilidad Masculina , Espermatogénesis/efectos de los fármacos , Espermidina/farmacología , Animales , Complicaciones de la Diabetes/tratamiento farmacológico , Complicaciones de la Diabetes/metabolismo , Complicaciones de la Diabetes/patología , Complicaciones de la Diabetes/fisiopatología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Infertilidad Masculina/tratamiento farmacológico , Infertilidad Masculina/etiología , Infertilidad Masculina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Análisis de Semen , Espermatogénesis/fisiología , Espermidina/uso terapéutico , Estreptozocina , Testículo/efectos de los fármacos , Testículo/metabolismoRESUMEN
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive paralysis due to motor neuron degeneration. It has been proposed that epigenetic modification and transcriptional dysregulation may contribute to motor neuron death. In this study, we investigate the basis for therapeutic approaches to target lysine-specific histone demethylase 1 (LSD1) and elucidate the mechanistic role of LSD1-histone H3K4 signaling pathway in ALS pathogenesis. METHODS: In order to examine the role of spermidine (SD), we administered SD to an animal model of ALS (G93A) and performed neuropathological analysis, body weight, and survival evaluation. RESULTS: Herein, we found that LSD1 activity is increased while levels of H3K4me2, a substrate of LSD1, is decreased in cellular and animal models of ALS. SD administration modulated the LSD1 activity and restored H3K4me2 levels in ChAT-positive motor neurons in the lumbar spinal cord of ALS mice. SD prevented cellular damage by improving the number and size of motor neurons in ALS mice. SD administration also reduced GFAP-positive astrogliogenesis in the white and gray matter of the lumbar spinal cord, improving the neuropathology of ALS mice. Moreover, SD administration improved the rotarod performance and gait analysis of ALS mice. Finally, SD administration delayed disease onset and prolonged the lifespan of ALS (G93A) transgenic mice. CONCLUSION: Together, modulating epigenetic targets such as LSD1 by small compounds may be a useful therapeutic strategy for treating ALS.
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Esclerosis Amiotrófica Lateral , Ratones , Animales , Esclerosis Amiotrófica Lateral/metabolismo , Espermidina/metabolismo , Espermidina/uso terapéutico , Histonas/metabolismo , Superóxido Dismutasa , Neuronas Motoras , Médula Espinal/metabolismo , Médula Espinal/patología , Ratones Transgénicos , Modelos Animales de EnfermedadRESUMEN
Rationale: Aging is one of the strongest risk factors for atherosclerosis. Yet whether aging increases the risk of atherosclerosis independently of chronic hyperlipidemia is not known. Objective: To determine if vascular aging before the induction of hyperlipidemia enhances atherogenesis. Methods and Results: We analyzed the aortas of young and aged normolipidemic wild type, disease-free mice and found that aging led to elevated IL (interleukin)-6 levels and mitochondrial dysfunction, associated with increased mitophagy and the associated protein Parkin. In aortic tissue culture, we found evidence that with aging mitochondrial dysfunction and IL-6 exist in a positive feedback loop. We triggered acute hyperlipidemia in aged and young mice by inducing liver-specific degradation of the LDL (low-density lipoprotein) receptor combined with a 10-week western diet and found that atherogenesis was enhanced in aged wild-type mice. Hyperlipidemia further reduced mitochondrial function and increased the levels of Parkin in the aortas of aged mice but not young mice. Genetic disruption of autophagy in smooth muscle cells of young mice exposed to hyperlipidemia led to increased aortic Parkin and IL-6 levels, impaired mitochondrial function, and enhanced atherogenesis. Importantly, enhancing mitophagy in aged, hyperlipidemic mice via oral administration of spermidine prevented the increase in aortic IL-6 and Parkin, attenuated mitochondrial dysfunction, and reduced atherogenesis. Conclusions: Before hyperlipidemia, aging elevates IL-6 and impairs mitochondrial function within the aorta, associated with enhanced mitophagy and increased Parkin levels. These age-associated changes prime the vasculature to exacerbate atherogenesis upon acute hyperlipidemia. Our work implies that novel therapeutics aimed at improving vascular mitochondrial bioenergetics or reducing inflammation before hyperlipidemia may reduce age-related atherosclerosis.
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Envejecimiento/metabolismo , Aterosclerosis/metabolismo , Endotelio Vascular/metabolismo , Lipoproteínas LDL/metabolismo , Mitocondrias/metabolismo , Envejecimiento/patología , Animales , Aorta/efectos de los fármacos , Aorta/metabolismo , Aorta/patología , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Dieta Alta en Grasa/efectos adversos , Endotelio Vascular/patología , Retroalimentación Fisiológica , Femenino , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Mitocondrias/patología , Mitofagia , Receptores de LDL/metabolismo , Espermidina/farmacología , Espermidina/uso terapéutico , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Intrauterine hypoxia (IUH) affects the growth and development of offspring. It remains unclear that how long the impact of IUH on cognitive function lasts and whether sexual differences exist. Spermidine (SPD) has shown to improve cognition, but its effect on the cognitive function of IUH offspring remains unknown. In the present study we investigated the influence of IUH on body weight and neurological, motor and cognitive function and the expression of APP, BACE1 and Tau5 proteins in brain tissues in 2- and 4-month-old IUH rat offspring, as well as the effects of SPD intervention on these parameters. IUH rat model was established by treating pregnant rats with intermittent hypoxia on gestational days 15-21, meanwhile pregnant rats were administered SPD (5 mg·kg-1·d-1;ip) for 7 days. Neurological deficits were assessed in the Longa scoring test; motor and cognitive functions were evaluated in coat hanger test and active avoidance test, respectively. We found that IUH decreased the body weight of rats in both sexes but merely impaired motor and cognitive function in female rats without changing neurological function in the rat offspring of either sex at 2 months of age. For 4-month-old offspring, IUH decreased body weight in males and impaired neurological function and increased cognitive function in both sexes. IUH did not affect APP, BACE1 or Tau5 protein expression in either the hippocampus or cortex of all offspring; however, it increased the cortical Tau5 level in 2-month-old female offspring. Surprisingly, SPD intervention prevented weight loss. SPD intervention reversed the motor and cognitive decline caused by IUH in 2-month-old female rat offspring. Taken together, IUH-induced cognitive decline in rat offspring is sex-dependent during puberty and can be recovered in adult rats. SPD intervention improves IUH-induced cognitive and neural function decline.
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Cognición/fisiología , Disfunción Cognitiva/tratamiento farmacológico , Hipoxia/fisiopatología , Espermidina/uso terapéutico , Útero/fisiopatología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Reacción de Prevención/efectos de los fármacos , Reacción de Prevención/fisiología , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Cognición/efectos de los fármacos , Disfunción Cognitiva/etiología , Femenino , Hipoxia/complicaciones , Masculino , Embarazo , Ratas Wistar , Factores Sexuales , Proteínas tau/metabolismoRESUMEN
Spermidine (SPD), a naturally occurring polyamine, has been recognized as a caloric restriction mimetic that confers health benefits, presumably by inducing autophagy. Recent studies have reported that oral administration of SPD protects against liver fibrosis and hepatocarcinogenesis through activation of microtubule associated protein 1S (MAP1S)-mediated autophagy. Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a transcription factor that mediates cellular protection by maintaining the cell's redox, metabolic, and proteostatic balance. In this study, we demonstrate that SPD is a noncanonical NRF2 inducer, and that MAP1S is a component of this noncanonical pathway of NRF2 activation. Mechanistically, MAP1S induces NRF2 signaling through two parallel mechanisms, both resulting in NRF2 stabilization: (1) MAP1S competes with Kelch-like ECH-associated protein 1 (KEAP1) for NRF2 binding through an ETGE motif, and (2) MAP1S accelerates p62-dependent degradation of KEAP1 by the autophagy pathway. We further demonstrate that SPD confers liver protection by enhancing NRF2 signaling. The importance of both NRF2 and p62-dependent autophagy in SPD-mediated liver protection was confirmed using a carbon tetrachloride-induced liver fibrosis model in wild-type, Nrf2-/- , p62-/- and Nrf2-/- ;p62-/- mice, as the protective effect of SPD was significantly reduced in NRF2 or p62 single knockout mice, and completely abolished in the double knockout mice. Conclusion: Our results demonstrate the pivotal role of NRF2 in mediating the health benefit of SPD, particularly in the context of liver pathologies.
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Cirrosis Hepática/tratamiento farmacológico , Hígado/efectos de los fármacos , Proteínas Asociadas a Microtúbulos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Espermidina/farmacología , Animales , Autofagia , Evaluación Preclínica de Medicamentos , Células HEK293 , Células Estrelladas Hepáticas/efectos de los fármacos , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Ratones , Proteínas Proto-Oncogénicas c-myc/metabolismo , Espermidina/uso terapéuticoRESUMEN
Traumatic brain injury (TBI) causes permanent neurological and cognitive impairments. Effective pharmacological interventions remain elusive. Spermidine is a polyamine compound found in our body that may play a role in brain development and congenital function. In this study, we aimed to investigate the therapeutic potential of spermidine for TBI. We employed experimental closed head injury (CHI) model to evaluate the protective function of spermidine on brain injury. We assessed the neurobehavioral function recovery using Neurologic Severity Score (NSS) and Morris water maze test. At histological level, we evaluated the improvement on brain edema, brain-blood barrier integrity, and cell apoptosis. We also measured inflammatory cytokines and brain injury biomarkers to monitor the treatment outcomes. Last, we correlated the level of spermidine with CHI animal model and TBI patients with different levels of severity. Spermidine administration post-CHI was found effectively to accelerate NSS improvement and shorten latency in maze test. We observed consistent improvements in brain edema, BBB function, and cell death in spermidine-treated group. Inflammatory cytokines and TBI biomarkers, e.g., S100B, MBP and CFAP were reduced significantly in treatment group. Interestingly, inhibiting spermidine synthesis influenced the neurobehavioral recovery in CHI mice. ODC1, a rate-limiting enzyme for spermidine synthesis, was found lower in CHI mice. Serum level of spermidine was significantly lower in TBI patients with severe pathological scores. Spermidine pathway may carry an endogenous role in pathophysiological process of CHI. For the first time, we demonstrated that administrating spermidine may provide a new treatment for TBI.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Espermidina/uso terapéutico , Adulto , Animales , Lesiones Traumáticas del Encéfalo/sangre , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones Endogámicos BALB C , Proteínas del Tejido Nervioso/sangre , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Espermidina/sangre , Espermidina/química , Espermidina/farmacologíaRESUMEN
Cardiovascular diseases are the most prominent maladies in aging societies. Indeed, aging promotes the structural and functional declines of both the heart and the blood circulation system. In this review, we revise the contribution of known longevity pathways to cardiovascular health and delineate the possibilities to interfere with them. In particular, we evaluate autophagy, the intracellular catabolic recycling system associated with life- and health-span extension. We present genetic models, pharmacological interventions, and dietary strategies that block, reduce, or enhance autophagy upon age-related cardiovascular deterioration. Caloric restriction or caloric restriction mimetics like metformin, spermidine, and rapamycin (all of which trigger autophagy) are among the most promising cardioprotective interventions during aging. We conclude that autophagy is a fundamental process to ensure cardiac and vascular health during aging and outline its putative therapeutic importance.
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Envejecimiento/patología , Autofagia , Enfermedades Cardiovasculares/patología , Sistema Cardiovascular/patología , Factores de Edad , Envejecimiento/metabolismo , Animales , Autofagia/efectos de los fármacos , Restricción Calórica , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Enfermedades Cardiovasculares/prevención & control , Sistema Cardiovascular/efectos de los fármacos , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/fisiopatología , Estado de Salud , Humanos , Longevidad , Metformina/uso terapéutico , Factores Protectores , Factores de Riesgo , Sirolimus/uso terapéutico , Espermidina/uso terapéuticoRESUMEN
Background: (R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. Methods: The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. Results: A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Conclusions: Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions.
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Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Antagonistas de Aminoácidos Excitadores/farmacología , Desamparo Adquirido , Ketamina/farmacología , Espermidina/análogos & derivados , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Ketamina/análogos & derivados , Masculino , Uso Fuera de lo Indicado , Ratas , Espermidina/química , Espermidina/uso terapéutico , Factores de TiempoRESUMEN
Polyamines are essential for cell growth and differentiation. They play important roles in protection from liver damage and promotion of liver regeneration. However, little is known about the effect of oral exogenous polyamine administration on liver damage and regeneration. This study investigated the impact of polyamines (spermidine and spermine) on ischemia/reperfusion injury (IRI) and liver regeneration. We used a rat model in which a 70% hepatectomy after 40 minutes of ischemia was performed to mimic the clinical condition of living donor partial liver transplantation (LT). Male Lewis rats were separated into 2 groups: a polyamine group given polyamines before and after operation as treatment and a vehicle group given distilled water as placebo. The levels of serum aspartate aminotransferase and alanine aminotransferase at 6, 24, and 48 hours after reperfusion were significantly lower in the polyamine group compared with those in the vehicle group. Polyamine treatment reduced the expression of several proinflammatory cytokines and chemokines at 6 hours after reperfusion. Histological analysis showed significantly less necrosis and apoptosis in the polyamine group at 6 hours after reperfusion. Sinusoidal endothelial cells were also well preserved in the polyamine group. In addition, the regeneration of the remnant liver at 24, 48, and 168 hours after reperfusion was significantly accelerated, and the Ki-67 labeling index and the expressions of proliferating cell nuclear antigen and phosphorylated retinoblastoma protein at 24 hours after reperfusion were significantly higher in the polyamine group compared with those in the vehicle group. In conclusion, perioperative oral polyamine administration attenuates liver IRI and promotes liver regeneration. It might be a new therapeutic option to improve the outcomes of partial LT. Liver Transplantation 22 1231-1244 2016 AASLD.
Asunto(s)
Regeneración Hepática/efectos de los fármacos , Trasplante de Hígado/efectos adversos , Daño por Reperfusión/prevención & control , Espermidina/uso terapéutico , Espermina/uso terapéutico , Administración Oral , Alanina Transaminasa/sangre , Animales , Apoptosis/efectos de los fármacos , Aspartato Aminotransferasas/sangre , Proliferación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Antígeno Ki-67/análisis , Hígado/patología , Trasplante de Hígado/métodos , Masculino , Necrosis/prevención & control , Antígeno Nuclear de Célula en Proliferación/análisis , Ratas , Ratas Endogámicas Lew , Daño por Reperfusión/sangre , Proteína de Retinoblastoma/análisis , Espermidina/administración & dosificación , Espermina/administración & dosificaciónRESUMEN
Chagas disease is a parasitic infection caused by the protozoa Trypanosoma cruzi that affects about 6 million people in Latin America. Despite its sanitary importance, there are currently only two drugs available for treatment: benznidazole and nifurtimox, both exhibiting serious adverse effects and limited efficacy in the chronic stage of the disease. Polyamines are ubiquitous to all living organisms where they participate in multiple basic functions such as biosynthesis of nucleic acids and proteins, proliferation and cell differentiation. T. cruzi is auxotroph for polyamines, which are taken up from the extracellular medium by efficient transporters and, to a large extent, incorporated into trypanothione (bis-glutathionylspermidine), the major redox cosubstrate of trypanosomatids. From a 268-compound database containing polyamine analogs with and without inhibitory effect on T. cruzi we have inferred classificatory models that were later applied in a virtual screening campaign to identify anti-trypanosomal compounds among drugs already used for other therapeutic indications (i.e. computer-guided drug repositioning) compiled in the DrugBank and Sweetlead databases. Five of the candidates identified with this strategy were evaluated in cellular models from different pathogenic trypanosomatids (T. cruzi wt, T. cruzi PAT12, T. brucei and Leishmania infantum), and in vitro models of aminoacid/polyamine transport assays and trypanothione synthetase inhibition assay. Triclabendazole, sertaconazole and paroxetine displayed inhibitory effects on the proliferation of T. cruzi (epimastigotes) and the uptake of putrescine by the parasite. They also interfered with the uptake of others aminoacids and the proliferation of infective T. brucei and L. infantum (promastigotes). Trypanothione synthetase was ruled out as molecular target for the anti-parasitic activity of these compounds.
Asunto(s)
Amida Sintasas/antagonistas & inhibidores , Enfermedad de Chagas/tratamiento farmacológico , Reposicionamiento de Medicamentos , Poliaminas/química , Amida Sintasas/química , Antiprotozoarios/química , Enfermedad de Chagas/parasitología , Simulación por Computador , Glutatión/análogos & derivados , Glutatión/química , Glutatión/uso terapéutico , Humanos , Imidazoles/química , Imidazoles/uso terapéutico , Nitroimidazoles/química , Nitroimidazoles/uso terapéutico , Poliaminas/uso terapéutico , Espermidina/análogos & derivados , Espermidina/química , Espermidina/uso terapéutico , Tiofenos/química , Tiofenos/uso terapéutico , Trypanosoma cruzi/efectos de los fármacos , Trypanosoma cruzi/patogenicidad , Interfaz Usuario-ComputadorRESUMEN
Of the biogenic polyamines, spermidine is a natural constituent of living cells and organisms. Spermidine is associated with regulation of cell growth, proliferation and differentiation, and with the suppression of oxidation and inflammation. Atopic dermatitis (AD) is a chronic inflammatory skin disease that has a complex and multiple pathogenesis, which includes genetic abnormality, modified or abnormal immune response and the production of nitric oxide and reactive oxygen species. We investigated whether spermidine can relieve AD-like clinical manifestation induced by the continual application of 2,4-dinitrofluorobenzene (DNFB) in NC/Nga mice. Spermidine at concentrations of 1 or 10 mg/kg reduced increasing ear swelling and attenuated oedema, haemorrhage and hyperkeratosis in AD-like skin lesions. Repetitive application of DNFB induced inflammatory cell infiltration to skin lesions, whereas intraperitoneal injection of spermidine inhibited DNFB-evoked infiltration of eosinophils, mast cells and T lymphocytes. Furthermore, spermidine suppressed mast cell degranulation and production of interferon-gamma by activated CD4(+) T cells in AD-like skin lesions. Spermidine may be a potential therapeutic agent for treatment of AD.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Dermatitis Atópica/inmunología , Dinitrofluorobenceno/administración & dosificación , Espermidina/farmacología , Animales , Dermatitis Atópica/inducido químicamente , Dermatitis Atópica/tratamiento farmacológico , Histocitoquímica , Inmunoglobulina E/sangre , Interferón gamma/sangre , Interleucina-4/sangre , Masculino , Ratones , Distribución Aleatoria , Organismos Libres de Patógenos Específicos , Espermidina/uso terapéuticoAsunto(s)
Autofagia/efectos de los fármacos , Enfermedades Cardiovasculares/tratamiento farmacológico , Sistema Cardiovascular/efectos de los fármacos , Polifenoles/uso terapéutico , Espermidina/uso terapéutico , Trehalosa/uso terapéutico , Animales , Proteínas Relacionadas con la Autofagia/metabolismo , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Enfermedades Cardiovasculares/fisiopatología , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patología , Sistema Cardiovascular/fisiopatología , Humanos , Polifenoles/efectos adversos , Transducción de Señal/efectos de los fármacos , Espermidina/efectos adversos , Trehalosa/efectos adversosRESUMEN
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a fatal neurodegenerative disease that causes loss of balance and motor co-ordination, eventually leading to paralysis. It is caused by the autosomal dominant inheritance of a long CAG trinucleotide repeat sequence within the ATXN3 gene, encoding for an expanded polyglutamine (polyQ) repeat sequence within the ataxin-3 protein. Ataxin-3 containing an expanded polyQ repeat is known to be highly prone to intraneuronal aggregation, and previous studies have demonstrated that protein quality control pathways, such as autophagy, are impaired in MJD patients and animal models of the disease. In this study, we tested the therapeutic potential of spermidine on zebrafish and rodent models of MJD to determine its capacity to induce autophagy and improve functional output. Spermidine treatment of transgenic MJD zebrafish induced autophagy and resulted in increased distances swum by the MJD zebrafish. Interestingly, treatment of the CMVMJD135 mouse model of MJD with spermidine added to drinking water did not produce any improvement in motor behaviour assays, neurological testing or neuropathology. In fact, wild type mice treated with spermidine were found to have decreased rotarod performance when compared to control animals. Immunoblot analysis of protein lysates extracted from mouse cerebellar tissue found little differences between the groups, except for an increased level of phospho-ULK1 in spermidine treated animals, suggesting that autophagy was indeed induced. As we detected decreased motor performance in wild type mice following treatment with spermidine, we conducted follow up studies into the effects of spermidine treatment in zebrafish. Interestingly, we found that in addition to inducing autophagy, spermidine treatment also induced apoptosis, particularly in wild type zebrafish. These findings suggest that spermidine treatment may not be therapeutically beneficial for the treatment of MJD, and in fact warrants caution due to the potential negative side effects caused by induction of apoptosis.
Asunto(s)
Enfermedad de Machado-Joseph , Enfermedades Neurodegenerativas , Humanos , Animales , Ratones , Espermidina/farmacología , Espermidina/uso terapéutico , Pez Cebra , Apoptosis , Autofagia , Modelos Animales de EnfermedadRESUMEN
PURPOSE: The combination of cisplatin and gemcitabine-based chemotherapy has been recommended as a preferred regimen for pancreatic ductal adenocarcinoma (PDAC) patients with germline-based mutations. However, the underlying mechanism remains poorly elucidated. Therefore, our study aimed to explore the mechanistic basis of the cell-killing activity of gemcitabine plus cisplatin and identify potential therapeutic targets. METHODS: First, we explored the synergistic cytotoxic effects of gemcitabine and cisplatin on PDAC through in vitro and in vivo experiments. Then, we investigated ferroptosis-related biomarkers, to assess the impact of the combination therapy on ferroptosis. Using bioinformatics methods, we identified SAT1 as a potential key mediator of ferroptosis induced by gemcitabine and cisplatin. We tested the polyamine levels in PDAC cells by LC-MS after overexpressed or knocked down SAT1, and explored the role of polyamines in ferroptosis using exogenous supplementation. Finally, we explored the regulatory effect of Sp1 on SAT1 through ChIP-qPCR and dual-luciferase reporter assay. RESULTS: Gemcitabine plus cisplatin enhanced cell death and induced ferroptosis in PDAC. This combination upregulated SAT1 transcription by inhibiting Sp1. SAT1 activation promoted the catabolism of spermine and spermidine, leading to iron accumulation and lipid peroxide generation, ultimately resulting in ferroptosis. CONCLUSIONS: In summary, our findings suggested the gemcitabine and cisplatin combination therapy induced ferroptosis in a GSH-independent manner in PDAC. The combined treatment inhibited Sp1 and upregulated SAT1 transcription, leading to the breakdown of spermine and spermidine. Therefore, targeting SAT1-induced polyamine metabolism may represent a promising therapeutic strategy for PDAC.
Asunto(s)
Carcinoma Ductal Pancreático , Ferroptosis , Neoplasias Pancreáticas , Humanos , Gemcitabina , Cisplatino/farmacología , Cisplatino/uso terapéutico , Espermina/uso terapéutico , Espermidina/metabolismo , Espermidina/uso terapéutico , Línea Celular Tumoral , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Poliaminas/metabolismo , Desoxicitidina/farmacología , Desoxicitidina/uso terapéuticoRESUMEN
OBJECTIVE: Spermidine (SPD) is an anti-aging natural substance, and it exerts effects through anti-apoptosis and anti-inflammation. However, the specific protective mechanism of SPD in osteoarthritis (OA) remains unclear. Here, we explored the role of SPD on the articular cartilage and the synovial tissue, and tested whether the drug would regulate the polarization of synovial macrophages by in vivo and in vitro experiments. METHODS: By constructing an OA model in mice, we preliminarily explored the protective effect of SPD on the articular cartilage and the synovial tissue. Meanwhile, we isolated and cultured human primary chondrocytes and bone marrow-derived macrophages (BMDMs), and prepared a conditioned medium (CM) to explore the specific protective effect of SPD in vitro. RESULTS: We found that SPD alleviated cartilage degeneration and synovitis, increased M2 polarization and decreased M1 polarization in synovial macrophages. In vitro experiments, SPD inhibited ERK MAPK and p65/NF-κB signaling in macrophages, and transformed macrophages from M1 to M2 subtypes. Interestingly, SPD had no direct protective effect on chondrocytes in vitro; however, the conditioned medium (CM) from M1 macrophages treated with SPD promoted the anabolism and inhibited the catabolism of chondrocytes. Moreover, this CM markedly suppressed IL-1ß-induced p38/JNK MAPK signaling pathway activation in chondrocytes. CONCLUSIONS: This work provides new perspectives on the role of SPD in OA. SPD does not directly target chondrocytes, but can ameliorate the degradation of articular cartilage through regulating M1/M2 polarization of synovial macrophages. Hence, SPD is expected to be the potential therapy for OA.